Amorphous esters of (+)-(SR, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid are known compounds. There is no disclosure in the prior art of any crystalline form, and particularly not an acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid.
It is recognized in the general art of crystallization of chemical compounds which include the instant acetoxymethyl and pivaloyloxymethyl esters of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo [3.2.0 ]hept-2-ene-2 carboxylic acid that "it is very difficult, though not absolutely impossible, to predict which crystal form is taken by a chemical substance which has never crystallized" as well as "the first crystal is often difficult to obtain of a newly discovered or synthesized chemical substance . . . once crystallization is successfuly achieved somewhere in the world, the substance becomes easily crystallizable; crystallization becomes easier and easier as the crystallization frequency increases" as stated by Prof. Rupert Sheldrake in The New Scientists (1989), "cephalosporins are often difficult to obtain in crystalline form and, even when crystallized, the products may be partially amorphous" as stated in Jour. Pharm. Sciences, 66, p. 1312 [near bottom left column] (1977) and "attempts to prepare cefamandole sodium in crystalline form suitable for commercial use with respect to purity and long-term stability were unsuccessful" as stated in Jour. Pharm. Sciences, 65, p. 1175 (1976).
There is a recognition in the art that any crystallization of penem compounds is often attainable, if at all, only with inventive skill, i.e., one of ordinary skill in the art is often not able to synthesize a crystalline form of a given penem compound. There is no relevant teaching in the prior art known to applicants that relates to a compound structurally close to either the acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid that leads to the synthesis set forth in this specification for the preparation of the crystalline acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid. Applicants have considered the patents to both Jenkins, U.S. Pat. No. 4,634,556 ("Jenkins") and Lang, U.S. Pat. No. 4,826,832 ("Lang") which teach away from the successful synthesis of the crystalline acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo [3.2.0 ]hept-2-ene-2 carboxylic acid. Considering the Jenkins patent, it is remote from the instant esters in terms of being an entirely different structure which does not provide motivation leading to the instant invention. First, Jenkins has a carbamoyloxyethylthio group which is neither an aromatic group nor a cyclic group but only a chain group attached with a sulfur atom to the 2-position of the penera nucleus, while Lang has either a 3-(or 4)-pyridyl group which is an aromatic heterocyclic group attached to the carbon atom at the same R.sup.3 position. Second, the gross structural differences between Lang and Jenkins do not permit their combination for any teaching insofar as any predictability is concerned for the creation of a crystalline form as per the present invention, inter alia, the carbamoyloxyethylthio group is entirely different from a pyridyl group as one is not aromatic whereas the other is, one is non-cyclic while the other is heterocyclic and one is bonded through carbon while the other is bonded through sulfur. Third, Jenkins teaches a structure that is grossly different from the instant acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid ester in that Jenkins' compound is a simple sodium salt EQU --COONa
whereas the instant compounds are each an oxymethyl ester EQU --COOCH.sub.2 O--.
Fourth, the instant esters are from a (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo [3.2.0]hept- 2-ene-2-carboxylic acid whereas Jenkins' compound has at the 3-position the group EQU --S--CH.sub.2 --CH.sub.2 --C(.dbd.O)--NH.sub.2
which is grossly dissimilar from the pyridyl required in the compound acetoxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid. Fifth, it is further manifested to a worker skilled in the art that salts and esters in the penem field will have differing solubilities to further remove any predictive value from Jenkins vis a vis crystallization of the instant compound and manifestly is not combinable with any teachings of Lang insofar as the instant invention is concerned. The prior art, taken alone or together with the skill of a worker in the art, does not provide a basis for the synthesis of any crystalline acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid.
One of ordinary skill in the art, given his ordinary skill and the teachings of the prior art, would not have been able to synthesize any crystalline acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid in any form. Crystalline acetoxymethyl or pivaloyloxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid provides advantages over the amorphous form of the same compound because only the crystalline form is capable of prolonged storage without disintegration as manifested by color changes and the amorphous form is not attainable in the same level of purity as the crystalline form. The superior properties of the crystalline form make such form suitable as a medication whereas an amorphous form of this compound is unsuitable for general medicinal use.
The tests set forth below confirm that whereas the amorphous compound of Reference Example 4 was unstable after three days when measured at extreme temperatures of 40.degree. C., 50.degree. C. and 60.degree. C. showing residual rate values of 95.6%, 83.7% and 55.8%, respectively, the crystalline acetoxymethyl ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl-]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid demonstrated storage stability under the identical conditions of in excess of 100.0%, i.e., measured at 40.degree. C., 50.degree. C. and 60.degree. C., storage stability was 101.9%, 101.7% and 102.2%, respectively. The test of the foregoing paragraph are standard industry tests to determine storage stability, and the results of the test indicate that the amorphous powder is not storage stable and therefor not satisfactory to be marketed as a pharmaceutical while the instant crystalline acetoxymethyl ester of (+)-(5R, 6S)-6-[ (R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-e ne-2-carboxylic acid is storage stable.
It is also noted that the sodium salt of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid is known. However, the sodium salt is not used in the method of the invention to make a crystalline ester of (+)-(5R, 6S)-6-[(R)-1-hydroxyethyl]-3-(3-pyridyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]h ept-2-ene-2-carboxylic acid. It has been discovered that the potassium salt provides unexpectedly easier crystallization and improved yield and reactivity in comparison to the sodium salt.